ISCHEMIC STROKE / CLASSIFICATION AND ETIOPATHOGENESIS

Stroke and celiac disease

David Goldemund M.D.
Updated on 07/11/2023, published on 16/02/2023

Celiac disease is a rare cause of ischemic stroke, and it may occur even in the absence of gastrointestinal symptoms

It is essential to consider this diagnosis with regard to the manageability of the disease with dietary measures

Introduction

celiac disease (also known as gluten enteropathy, endemic sprue, or primary malabsorption syndrome) is an immune-mediated systemic disease triggered by gluten in genetically susceptible individuals
- this response results in characteristic damage to the villi, leading to malabsorption
it is characterized by a variable combination of clinical symptoms in the presence of specific antibodies, HLA-DQ2 or HLA-DQ8 haplotypes, and enteropathy
heterogeneous clinical signs and symptoms can manifest in either childhood or adulthood; the disease may also be asymptomatic
celiac disease is associated with an increased incidence of cardiovascular diseases, including stroke (OR 1.4) [El Moutawakil, 2009] [Fabbri, 2012] [Medscape, 2014]
- stroke may occur without clinical signs of malabsorption (both in adulthood and childhood)
gluten intolerance is lifelong and incurable, but symptoms resolve with adherence to a gluten-free diet

Stroke and celiac disease

celiac disease is associated with an increased risk of venous and arterial thromboembolism (HR for stroke being 1.45) [Poulin, 2015]
- exact relationship between celiac disease and stroke and its clinical significance remain areas of ongoing research
young patients with cryptogenic stroke might be evaluated for celiac disease (especially if they have other suggestive symptoms or family history)
possible mechanisms of vascular involvement:
- the chronic inflammatory state may contribute to endothelial dysfunction and a prothrombotic state
- malabsorption in celiac disease can lead to deficiencies in essential vitamins and nutrients, such as vitamin B12, which may be linked to hyperhomocysteinemia, a potential risk factor for stroke
- coagulation abnormalities
- increased risk of other cardiovascular diseases, which could indirectly increase the risk of ischemic stroke
- CNS vasculitis
diet reduces the risk of associated complications, including vascular events

Clinical presentation

when food containing gluten is consumed, the lining of the small intestine becomes inflamed, and the epithelial cells of the intestine are damaged
as a result, nutrients may be difficult to absorb and remain undigested in the intestine
symptoms:
- weight loss
- diarrhea
- vomiting, loss of appetite, fatigue
- neurological symptoms (epilepsy, bilateral occipital calcification, cerebellar ataxia, degenerative central nervous system disease, peripheric neuropathy, myopathy, and stroke)
  - neurological symptoms may occur even without prior signs of malabsorption. !!
celiac disease is associated with an increased risk of:
- non-Hodgkin’s lymphoma
- diabetes
- Hashimoto’s thyroiditis
- dermatitis herpetiformis Duhring
- dilated cardiomyopathy (increased incidence of CD in patients with idiopathic dilated cardiomyopathy as well as in patients with secondary cardiomyopathy has been reported recently) (Frustaci, 2002)

Diagnostic evaluation

Antibodies detection

test antibodies against tissue transglutaminase (anti-TG2 or anti-tTG) and endomysium (EMA) in blood, or antibodies against deamidated gliadin peptides (DGP)
- tTG is an enzyme that modifies gluten peptides, making them more immunogenic. In celiac disease, the immune system mistakenly targets and attacks this enzyme, leading to the production of anti-tTG antibodies
- the EMA test is highly specific for celiac disease but is more labor-intensive
- the DGP test may be useful in cases where traditional antibody tests are unclear, especially in children < 2 years of age
- anti-gliadin antibodies (AGA) have been abandoned due to their low specificity
initially, test for total IgA and anti-TG2 in the IgA class
- the test is important because some people (∼ 2-3% of celiac patients) are deficient in IgA, which can lead to false-negative results in the IgA-tTG and IgA-EMA tests
- in the presence of IgA deficiency (< 0.2 g/L), test for EMA and anti-TG2 in the IgG class (or anti-DGP antibodies)
a decline in antibody levels typically indicates that the patient is adhering to a gluten-free diet and that the intestine is healing

HLA identification (Human Leukocyte Antigen)

HLA-DQ2 (found in 95% of patients) and HLA-DQ8 (5% of patients) are strongly associated with celiac disease
their presence alone does not confirm the disease – HLA-DQ2 or HLA-DQ8 positivity is very common (25-40% of the population)) and only a fraction of these individuals develop celiac disease (these HLA types are necessary for the disease’s development but not sufficient on their own)
HLA-DQ2 and HLA-DQ8 negativity virtually excludes the diagnosis of celiac disease
first-degree relatives of individuals with celiac disease are at an increased risk of developing the disease; in these individuals, HLA typing may be a useful screening tool

Biopsy

analysis of duodenal biopsy is the gold standard, especially in elderly patients
typical finding includes villous atrophy with hyperplasia of the crypts and an increased intraepithelial lymphocyte count

All tests should be performed before the patient starts a gluten-free diet

The indicative blood test for the presence of IgA transglutaminase antibodies can be done at home (tests are available over the counter). However, it should not replace a professional medical evaluation.

Management

a gluten-free diet is crucial; with adherence to the diet, the intestine heals, reducing the risk of long-term complications
patients should be informed about potential vascular risks and should be managed for traditional vascular risk factors
if vasculitis is confirmed, additional treatments like immunosuppressive drugs might be considered based on the severity and the patient’s clinical presentation